Molecular Human Reproduction, Vol. 6, No. 7, 642-647,
July 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Decreased superoxide dismutase expression and increased concentrations of lipid peroxide and prostaglandin F2
in the decidua of failed pregnancy
Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan
Abstract
To study the possible role of the superoxide radical and its scavenging system in the decidua of early pregnancy, superoxide dismutase (SOD) values and concentrations of lipid peroxide and prostaglandin F2
(PGF2) were analysed in the decidua obtained from normal pregnancy and failed pregnancy. Failed pregnancy was divided into two groups; spontaneous abortion with or without vaginal bleeding. In the spontaneous abortion with vaginal bleeding, total SOD activities, Cu,Zn-SOD activities and Cu,Zn-SOD mRNA values in the decidua were significantly lower, and concentrations of lipid peroxide and PGF2 were significantly higher, than those in the normal pregnancy and the spontaneous abortion without vaginal bleeding. In contrast, activities and mRNA values of Mn-SOD were significantly higher in the spontaneous abortion with vaginal bleeding than the other two groups. There was no significant difference in all of these parameters between the normal pregnancy and the spontaneous abortion without vaginal bleeding. In conclusion, the decrease in Cu,Zn-SOD expression and the increase in lipid peroxide in the decidua could be involved in the termination of spontaneous abortion, mediated through the increase in PGF2 synthesis. In other words, Cu,Zn-SOD may contribute to the maintenance of pregnancy by preventing the accumulation of superoxide radicals that cause PGF2 synthesis.
decidua/prostaglandin F2/spontaneous abortion/superoxide dismutase/superoxide radical
Introduction
It is well known that superoxide radicals cause tissue damage, whereas superoxide dismutase (SOD) works protectively by scavenging superoxide radicals. Recent evidence has shown that the superoxide radical and its scavenging system play important roles in reproductive function (Riley and Behrman, 1991
; Shimamura et al., 1995; Sugino et al., 1996a; Kato et al., 1997; Suzuki et al., 1999). In the human uterus, reactive oxygen species including superoxide radicals are generated in the endometrium (Benedetto et al., 1981; Sugino et al., 1996b). The human endometrium has also copper-zinc SOD (Cu,Zn-SOD), located in the cytosol, and manganese SOD (Mn-SOD), located in the mitochondria (Sugino et al., 1996b; Telfer et al., 1997). Both SODs belong to a first enzymatic step that protects cells against toxic oxygen radicals. Reactive oxygen species are increased in the late secretory phase endometrium, just before menstruation, and decreased in the decidua in early pregnancy (Sugino et al., 1996b). SOD activities are low in the late secretory phase endometrium, whereas they are high in the decidua in early pregnancy (Sugino et al., 1996b). These findings suggest that SOD may play important roles in the stability of human endometrial tissue and that the accumulation of reactive oxygen species may be involved in endometrial shedding. We have also shown by immunohistochemical studies that SOD is preferentially expressed in (pre) decidual cells (Sugino et al., 1996b) and that SOD is induced in the endometrial stromal cell by in-vitro decidualization (Sugino et al., 2000b). It therefore seems that decidual SOD plays important roles in the decidual function and the maintenance of early pregnancy.
Spontaneous abortion is the most common complication of early pregnancy. In spontaneous abortion, expulsion of the uterine content will occur to terminate pregnancy, usually accompanied by uterine contraction. However, there is a case, so-called missed abortion, in which dead products of conception are retained in the uterus without bleeding for several weeks. Thus, the exact mechanism responsible for the spontaneous expulsion is not clearly clarified. It is well known that uterine contraction can be caused by prostaglandin F2 (PGF2) and it is of interest to note that PGF2 synthesis can be stimulated by reactive oxygen species (Hemler et al., 1979; Hemler and Lands, 1980; Cherouny et al., 1988). Therefore, to study the possible role of the superoxide and its scavenging system in the decidua and the pathophysiology of failed pregnancy, we decided to examine the relationship between SOD expression, reactive oxygen species and PGF2 in the decidua of failed pregnancy.
Materials and methods
This project was reviewed and approved by the committee of investigations involving human subjects of Yamaguchi University School of Medicine. Informed consent from the patient was obtained before collection of any tissue samples for this study.
Reagents
Moloney murine leukaemia virus reverse-transcriptase and deoxynucleotide triphosphates were obtained from Life Technologies Inc (Grand Island, NY, USA) random hexamer and Taq DNA polymerase from Perkin-Elmer Co (Foster City, CA, USA); [-32P]-deoxycytidine triphosphate (dCTP) from Amersham (Arlington Heights, IL, USA); Isogen from Wako Pure Chemical Industries Ltd (Osaka, Japan); and high performance liquid chromatography-grade acetonitrile was obtained from Nacalai Tesque Co Ltd (Kyoto, Japan).
Decidual tissue samples
Decidual tissues were obtained by dilatation and curettage from: (i) 11 women of normal pregnancy (7–10 weeks), aged 18–38 years; (ii) 12 patients of spontaneous abortion without vaginal bleeding (8 –10 weeks), aged 23–37 years; and (iii) 12 patients of spontaneous abortion with vaginal bleeding (6–10 weeks), aged 27–41 years. Tissue samples were washed with saline to remove blood, and immediately frozen in liquid nitrogen and stored at –80°C until SOD activity assay, lipid peroxide assay, PGF2 assay and RNA isolation. In some patients, blood samples were obtained at curettage for determination of serum human chorionic gonadotrophin (HCG) and progesterone concentrations.
SOD assay and lipid peroxide assay
Decidual tissues were homogenized with Tris–HCl buffer (0.01 mol/l, pH 7.4) using glass homogenizers and centrifuged at 800 g for 10 min at 4°C, and the supernatant was used for SOD assay. Cu,Zn-SOD and Mn-SOD activities were determined as reported previously (Sugino et al., 1993a). The amount of protein required for 50% inhibition in the absorbance at 550 nm was defined as one unit (nitrite unit; NU) of SOD activity. All data were expressed in NU of SOD activity per mg protein. Protein concentrations were determined by Lowry's method (Lowry et al., 1951). The intra- and inter-assay coefficients of variation were 3.8 and 9.6%, for the Cu,Zn-SOD assay, and 4.7 and 6.4% for the Mn-SOD assay respectively.
Concentrations of lipid peroxide in the decidual tissue were measured by the thiobarbituric acid method as reported previously (Sugino et al., 1993a). The results were expressed as nmol of malondialdehyde (MDA) per g wet weight.
Reverse transcription–polymerase chain reaction (RT–PCR)
Total RNA was isolated from the decidual tissue with Isogen by the method provided by the manufacturer. For mRNA analysis, RT–PCR was performed as reported previously (Sugino et al., 2000a). The oligonucleotide primers for Cu,Zn-SOD (5'-CGAGCAGAAGGAAAGTAATG-3' and 5'-TAGCAGGATAACAGATGAGT-3') and for Mn-SOD (5'-AGTTCAATGGTGGTGGTCATA-3' and 5'-CAATCCCCAGCAGTGGAATAA-3') were designed on the basis of the human Cu,Zn-SOD (Hallewell et al., 1985) and Mn-SOD cDNA sequences (Gene Bank, accession NO. E01408). Two oligonucleotide primers (5'-CTGAAGGTCAAAGGGAATGTG-3' and 5'-GGACAGAGTCTTGATGATCTC-3') were also used to amplify ribosomal protein L19 as an internal control as reported previously (Chan et al., 1987). In brief, 3 µg of total RNA were reverse-transcribed at 42°C in a reaction mixture (single-strength PCR buffer, 2.5 mmol/l deoxynucleotide triphosphates, 5 µmol/l random hexamer primer, 1.5 mmol/l MgCl2, and 200 IU Moloney murine leukaemia virus reverse-transcriptase). The RT product was divided into two equal aliquots and placed in two tubes for SOD primers and L19 primers, and PCR was performed. For PCR amplification, a mixture containing the oligonucleotide primers (50 pmol), [-32P]dCTP (2 µCi at 3000 Ci/mmol), and Taq DNA polymerase (2.5 IU) was added to each reaction. Amplification was carried out for 25 cycles consisting of 95°C (1 min), 52°C (1 min) and 72°C (1 min) for Cu,Zn-SOD and 25 cycles consisting of 95°C (1 min), 54°C (1 min) and 72°C (1 min) for Mn-SOD followed by 10 min of final extension at 72°C in a programmed temperature control system PC-800 (ASTEC, Fukuoka, Japan). The predicted sizes of the PCR-amplified products were 455 bp for Cu,Zn-SOD, 282 bp for Mn-SOD, and 194 bp for L19. A linear curve was plotted using number of cycles of amplification versus densitometric values of the PCR products, measured with a BAS2000 (Fuji Photo Film Co., Tokyo, Japan). The optimal number of cycles for amplification that fit within the linear range was chosen for each set of primers of SODs and L19 (data not shown). Reaction products were electrophoresed on an 8% polyacrylamide nondenaturing gel. After autoradiography, data were quantified using a bioimaging analyser BAS2000. To validate that the amplified cDNAs were Cu,Zn-SOD and Mn-SOD, the PCR products were cloned with TA cloning kit (Invitrogen Co., San Diego, CA, USA). Then direct sequence analyses of the PCR products were performed. The cDNA sequences of amplified cDNA with primers sets for Cu,Zn-SOD and Mn-SOD were consistent with the previously reported sequences of human Cu,Zn-SOD (Hallewell et al., 1985) and Mn-SOD (Gene Bank, accession NO. E01408).
PGF2 assay
Prostaglandins in the decidua were extracted by the method reported by Olofsson et al. (1990). In brief, decidual tissues were homogenized with 0.01 mol/l PBS (pH 3.0) and applied to a C18-LRC solid phase extraction cartridge (Bond-Elut, Varian Co., Harbor City, CA, USA), and the cartridge was rinsed by distilled water and 10% acetonitrile. Prostaglandins were then eluted with methanol and evaporated under nitrogen. The dried extract was dissolved with ethanol and the kit assay solution, and PGF2 concentrations were determined by a PGF2 enzyme immunoassay kit (Assay Designs, Inc., Ann. Arbor, MI, USA). The sensitivity of the assay was 4.6 pg/ml. The intra- and inter-assay coefficients of variation were 7.8 and 7.0% respectively. The results were expressed as ng of PGF2 per g wet weight.
Progesterone assay
Serum progesterone concentrations were determined by a specific radioimmunoassay as reported previously (Kato et al., 1982). The sensitivity of the assay was 100 pg/ml, and the intra- and inter-assay coefficients of variation were 7.0 and 14.4% respectively.
Statistical analysis
Data were examined by analysis of variance and Duncan's new multiple range test. P < 0.05 was considered to be statistically significant.
Results
In this study, spontaneous abortion was divided into two groups. One group was spontaneous abortion without vaginal bleeding (so-called missed abortion), which also has no symptoms such as abdominal pain. The other group was spontaneous abortion with vaginal bleeding, which is in the middle of spontaneous expulsion of uterine content. Table I shows the serum concentrations of HCG and progesterone in those groups. Serum HCG concentrations were significantly (P < 0.05) lower in the spontaneous abortion without vaginal bleeding group than the normal pregnancy group and much lower in the spontaneous abortion with vaginal bleeding group. There was no statistically significant difference in serum HCG concentrations between the spontaneous abortion groups. Serum progesterone concentrations were significantly (P < 0.01) lower in the spontaneous abortion without vaginal bleeding group than the normal pregnancy, and those in the spontaneous abortion with vaginal bleeding group were significantly (P < 0.05) lower than the spontaneous abortion without vaginal bleeding (Table I).
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Total SOD and Cu,Zn-SOD activities in the decidual tissue were significantly (P < 0.05 and P < 0.01 respectively) lower in the spontaneous abortion with vaginal bleeding group than the normal pregnancy or the spontaneous abortion without vaginal bleeding group (Figure 1A,B
). In contrast, Mn-SOD activities were significantly (P < 0.05) higher in the spontaneous abortion with vaginal bleeding group than other two groups (Figure 1C). To study whether those changes in SOD activities are controlled at the mRNA level, RT–PCR was performed. Cu,Zn-SOD mRNA expression in the decidual tissue was significantly (P < 0.01) lower in the spontaneous abortion with vaginal bleeding group than the normal pregnancy and the spontaneous abortion without vaginal bleeding group (Figure 2A), whereas Mn-SOD mRNA expression was significantly (P < 0.05) higher in the spontaneous abortion with vaginal bleeding group than in the other two groups (Figure 2B).
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Lipid peroxide concentrations in the decidual tissue were significantly (P < 0.01) higher in the spontaneous abortion with vaginal bleeding group than the normal pregnancy and the spontaneous abortion without vaginal bleeding group (Figure 3
).
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Since it has been reported that reactive oxygen species or their product, lipid peroxide, stimulate synthesis of PGF2
(Hemler et al., 1979; Hemler and Lands, 1980; Cherouny et al., 1988), we examined the PGF2 content in the decidual tissue in those groups. PGF2 concentrations in the decidual tissue were significantly (P < 0.01) higher in the spontaneous abortion with vaginal bleeding group than the normal pregnancy and the spontaneous abortion without vaginal bleeding group (Figure 4).
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Discussion
The present study showed a decreased Cu,Zn-SOD expression and an increased lipid peroxide concentration in the decidua in spontaneous abortion with vaginal bleeding, but not in spontaneous abortion without vaginal bleeding, suggesting that oxidative stress in the decidua may be involved in the termination of spontaneous abortion. Accumulation of lipid peroxides may cause not only tissue damage but also some biological events to accelerate the termination of pregnancy. It has been reported that reactive oxygen species or their product, lipid peroxide, stimulate synthesis of PGF2 that causes uterine contraction (Hemler et al., 1979; Hemler and Lands, 1980; Cherouny et al., 1988). The present study showed the increased PGF2 concentrations in the decidua of spontaneous abortion with vaginal bleeding. Thus, oxidative stress in the decidua may induce the termination of spontaneous abortion by increasing PGF2 synthesis. In other words, the present study may suggest that Cu,Zn-SOD in the decidua contributes to the maintenance of pregnancy by preventing the accumulation of lipid peroxides leading to PGF2 synthesis that inhibits uterine quiescence. This may be supported by the reports showing that the concentrations of PGF2 and lipid peroxide in the decidua in early pregnancy were significantly lower than those in the late secretory endometrium, just before endometrial shedding (Ishihara et al., 1986; Sugino et al., 1996b). The reason that some abortions, so-called missed abortion, do not terminate after fetal death is not clarified. The present study may provide a possible reason that oxidative stress and the subsequent PGF2 synthesis has not yet occurred in the decidua in missed abortion.
There may be other biological events involved in the termination of failed pregnancy. Interestingly, a recent report has shown that a decrease in type IV collagen was observed in the decidua of spontaneous abortion (Iwahashi et al., 1996). Since superoxide radicals have been reported to stimulate collagenase activities (Owens et al., 1997), oxidative stress in the decidua may be involved in the termination of spontaneous abortion mediated through the decrease in type IV collagen. It is also of interest to note a recent report that spontaneous abortion may be associated with apoptosis (Kokawa et al., 1998). It has been reported that superoxide radicals induce apoptosis (Rothstein et al., 1994; Troy and Shelanski, 1994; Sugino et al., 1999). Therefore, there may be a possibility that superoxide radicals stimulate decidual apoptosis, which in turn accelerates the termination of failed pregnancy. However, further studies are needed regarding the biological events caused by oxidative stress in the decidua in failed pregnancy.
It is difficult to clearly explain the mechanism by which decidual Cu,Zn-SOD expression was decreased in spontaneous abortion with vaginal bleeding. Low concentrations of HCG and progesterone may affect decidual Cu,Zn-SOD expression. Progesterone is important for decidualization that can stimulate SOD expression (Sugino et al., 2000b), and it has been reported that HCG promotes decidualization (Tang and Gurpide, 1993) and that HCG and placental luteotrophins stimulate Cu,Zn-SOD expression in the corpus luteum (Sugino et al., 1998b, 2000a; Takiguchi et al., 2000). Since there was no difference in decidual Cu,Zn-SOD concentrations between normal pregnancy and spontaneous abortion without vaginal bleeding whereas there was significant difference in serum HCG and progesterone concentrations between them, it may seem that HCG and progesterone are not related to decidual Cu,Zn-SOD expression. However, spontaneous abortion with vaginal bleeding showed much lower serum concentrations of HCG and progesterone together with the decreased expression of Cu,Zn-SOD. Thus, there may be an alternative possibility that the concentration of HCG and progesterone in the spontaneous abortion with vaginal bleeding was too low to maintain Cu,Zn-SOD expression and the concentration in the spontaneous abortion without vaginal bleeding may have been enough to maintain it. Further studies are needed to better understand the involvement of HCG and progesterone in the regulation of decidual Cu,Zn-SOD in spontaneous abortion. It is also of interest to note another possibility that the decreased Cu,Zn-SOD expression in the decidua may be due to the decline in decidual blood flow. It has been reported that vascular occlusion is observed in the decidua as a change of terminal stage of spontaneous abortion (Salafia et al., 1993), and a decline in blood flow causes a decrease in Cu,Zn-SOD activity and an increase in reactive oxygen species in a variety of organs (McCord, 1985; Yoshikawa et al., 1989; Sugino et al., 1993b; Sugino and Kato, 1994).
In the present study, it seems that the change in Cu,Zn-SOD expression is more closely related with the change in lipid peroxide and PGF2 than is the change in Mn-SOD expression. Recent evidence has also shown that Cu,Zn-SOD knock-out mice have a high abortion rate, suggesting that Cu,Zn-SOD is important in the maintenance of early pregnancy (Ho et al., 1998). Interestingly, in contrast with Cu,Zn-SOD, Mn-SOD expression was higher in the group of spontaneous abortion with vaginal bleeding. This differential expression has been reported in the inflammatory environment, e.g. corpus luteum regression (Sugino et al., 1998a, 2000a) and ovulation (Sato et al., 1992). It is thought that Cu,Zn-SOD is a constitutive type and Mn-SOD is an inducible type that can be responsive to inflammatory reaction or cytokines (Sugino et al., 1998a). We have recently found that Mn-SOD, but not Cu,Zn-SOD, can be induced in the human decidualized stromal cell by cytokines (unpublished data). It is possible that Mn-SOD expression is modulated locally by mononuclear phagocytes or cytokines because macrophages infiltration is observed in the decidua of advanced spontaneous abortion (Novak et al., 1988; Salafia et al., 1993). Although the differential expression of Cu,Zn-SOD and Mn-SOD may suggest that they play different roles in the decidua, the specific role of Mn-SOD remains unknown.
In conclusion, the decrease in Cu,Zn-SOD expression and the increase in lipid peroxides in the decidua could be involved in the termination of spontaneous abortion, mediated through the increase in PGF2 synthesis. In other words, Cu,Zn-SOD in the decidua may contribute to the maintenance of pregnancy by preventing the accumulation of reactive oxygen species that cause PGF2 synthesis.
Acknowledgments
This work was supported in part by a grant from the UBE Foundation and Grant-in-Aid 11671623 from the Ministry of Education, Science, and Culture, Japan.
Notes
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan. E-mail: obgyn{at}po.cc.yamaguchi-u.ac.jp 
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